The Next Generation of JAK Inhibitors: an Update on Fedratinib, Momelotonib, and Pacritinib

Curr Hematol Malig Rep. 2020 Dec;15(6):409-418. doi: 10.1007/s11899-020-00596-z.

Abstract

Purpose of review: Ruxolitinib is the first FDA-approved JAK inhibitor for the treatment of myeloproliferative neoplasms and is an effective means of controlling symptom burden and improving splenomegaly. However, a majority of patients will develop disease progression with long-term use. Fedratinib, momelotinib, and pacritinib are three newer-generation JAK inhibitors being prospectively evaluated and we will discuss their roles in the treatment of myeloproliferative neoplasms.

Recent findings: Fedratinib has a role in both JAK-inhibitor naive intermediate-/high-risk myelofibrosis patients and in patients that have previously received ruxolitinib. It has recently received FDA approval for these indications as well. Momelotinib does not appear to have an advantage over ruxolitinib with regards to improving splenomegaly in intermediate-/high-risk JAK-inhibitor naive myelofibrosis. However, increased rates of transfusion independence have been noted with momelotinib. Pacritinib has been studied in myelofibrosis patients with significant baseline anemia and thrombocytopenia; these trials support the use of pacritinib in myelofibrosis patients with significant thrombocytopenia. While ruxolitinib is effective in reducing the symptom burden and splenomegaly of patients with myeloproliferative neoplasms, a majority of patients will ultimately progress on therapy. Newer-generation JAK inhibitors including fedratinib, momelotinib, and pacritinib are being prospectively evaluated to determine their appropriate roles in the management of myeloproliferative neoplasms. In addition, both combination therapies with JAK inhibitors and novel investigational therapies are being actively explored.

Keywords: Fedratinib; JAK inhibitors; Momelotinib; Myeloproliferative neoplasms; Pacritinib.

Publication types

  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzamides / pharmacology
  • Benzamides / therapeutic use*
  • Biomarkers
  • Bridged-Ring Compounds / pharmacology
  • Bridged-Ring Compounds / therapeutic use*
  • Clinical Trials as Topic
  • Disease Management
  • Disease Progression
  • Disease Susceptibility
  • Humans
  • Janus Kinase Inhibitors / pharmacology
  • Janus Kinase Inhibitors / therapeutic use*
  • Molecular Targeted Therapy / methods
  • Myeloproliferative Disorders / diagnosis
  • Myeloproliferative Disorders / drug therapy*
  • Myeloproliferative Disorders / etiology
  • Myeloproliferative Disorders / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use*
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*
  • Treatment Outcome

Substances

  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • Benzamides
  • Biomarkers
  • Bridged-Ring Compounds
  • Janus Kinase Inhibitors
  • Pyrimidines
  • Pyrrolidines
  • Sulfonamides
  • fedratinib
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide